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Morning akinesia in Parkinson’s disease: challenges

and solutions
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Journal of Parkinsonism and Restless Legs Syndrome
15 June 2016
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Nicola Tambasco 1 Abstract: Motor complications of Parkinson’s disease (PD) have been reported to occur
Simone Simoni 1 after a few years of treatment with levodopa (L-dopa). Morning akinesia is a delayed ON of
the first L-dopa daily dose, occurring in almost 60% of patients on dopaminergic treatment.
Pasquale Nigro 1 This is primarily a motor symptom, but has been recently recognized as being correlated with
Federico Paolini Paoletti 1 nonmotor fluctuations. Sleep disorders and gastrointestinal dysfunction might be the underly-
For personal use only.

Erica Marsili 1 ing mechanisms. Over the past 30 years, several pharmacological and nonpharmacological
approaches have been investigated.
Paolo Calabresi 1,2
Keywords: Parkinson’s disease, morning akinesia, motor fluctuation, L-dopa
1
Neurology Clinic, Azienda
Ospedaliera – Università di
Perugia, Perugia, 2Neurophysiology Introduction
Department, IRCCS Fondazione Santa
Lucia, Rome, Italy Most patients with Parkinson’s disease (PD) on levodopa (L-dopa) have motor fluctua-
tions. An improvement in symptoms after L-dopa administration is defined as “ON”,
whereas a return to symptoms is termed “OFF”,1 ie, when L-dopa (L-dopa) plasma
concentration decreases. OFF periods generally appear when the benefit from a given
L-dopa dose disappears prematurely (wearing OFF) or when the next L-dopa dose
produces a delayed onset of action (delayed ON).2,3 Delayed ON of the first L-dopa
daily dose is known as morning akinesia, and this condition can significantly affect
the quality of life (QoL) and impair daily activities, such as arising from bed, dressing,
bathing, toileting, preparing breakfast, and getting on with the day’s work.2Morning
akinesia is the most common, and often, the first motor complication of PD.2 It is noticed
at awakening after a nightlong treatment-free period, reflecting the dopaminergic noc-
turnal decline with insufficient nighttime storage or refreshing of the dopaminergic
system during nighttime and sleep.
Over the past 3 decades, several investigations have been carried out to understand
this symptomology.

Pathophysiology
Morning akinesia occurs in almost 60% of PD patients on dopaminergic treatment
Correspondence: Nicola Tambasco across all disease stages.3 Most of these patients have experienced longer durations of
Neurology Clinic, Azienda PD motor symptoms and are in moderate to advanced stages of disease, with the largest
Ospedaliera – Universitaria di Perugia,
Località Sant’Andrea delle Fratte, proportion of these patients classified according to the Hoehn and Yahr scale 2.5–3).3
06156 Perugia, Italy OFF periods are mainly characterized by motor symptoms and motor complica-
Tel +39 075 578 3830
Fax +39 075 578 4229
tions, although they have been recently attributed to nonmotor OFF and nonmotor
Email n.tambasco@libero.it fluctuations.3,4

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The optimization of dopaminergic treatment is also sialorrhoea, dysphagia, oesophageal dysmotility, gastro-
crucial. Peripheral and central factors underlie these oesophageal reflux, gastroparesis, constipation, and impaired
fluctuations. defecation.12 These gastrointestinal symptoms significantly
impair QoL in PD.16
The emerging role of nonmotor Gastroparesis, a condition where the stomach takes longer
aspects than normal to empty, is common in both early and advanced
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Nonmotor symptoms (NMSs) are often poorly understood PD patients, and may even be a marker of preclinical PD.17
and inadequately treated, but are thought to arise from a more Nonetheless, data concerning prevalence, relationship to the
diffused involvement of the central, autonomic, and enteric underlying disease process, relevance to PD management,
nervous systems.5 and optimal treatment of gastroparetic symptoms are still
The relevance of NMSs has recently been studied in 320 limited.13 In addition to causing gastrointestinal symptoms,
PD patients,3 with 88% of the patients reporting an associa- gastroparesis may cause motor fluctuations, including
tion between morning akinesia and NMSs. delayed ON and morning akinesia, by delaying the arrival of
The predominant NMSs associated with morning aki- oral L-dopa to intestinal absorptive sites.12,14,18–21
nesia are urgency of urination, anxiety, dribbling of saliva, To guarantee a high level of efficacy from oral L-dopa, it
pain, low mood, limb paresthesia, and dizziness. must be taken on an empty stomach so that it can be absorbed
Sleep disorders are often involved in triggering early into the proximal small intestine. Gastroparesis can cause a
morning OFF periods. PD patients have been reported to delay in L-dopa delivery to the duodenum, resulting in the
For personal use only.

have reduced total sleep times compared to healthy con- clinical phenomenon of delayed ON after a L-dopa dose.18
trols.6 Sleep efficiency is often reduced, with an increased Several studies have demonstrated a significant relationship
number of awakenings and an increased wakefulness after between gastric emptying and L-dopa pharmacokinetics in
sleep onset. Sleep fragmentation is the most consistent and PD patients, suggesting that delayed gastric emptying con-
often the earliest sleep disturbance in PD, with frequent tributes to delayed ON and other motor fluctuations.22–24
awakenings during the night, with often 30–40% of the time Other drugs, including dopamine agonists, anticholiner­
being awake. Up to 80% of PD patients report having 2–5 gics, amantadine, inhibitors of monoamine oxidase and
awakenings per night.7,8 Sleep disruption, thus, may easily catechol-O-methyltransferase (COMT), may also contribute
promote the appearance of nightlong rigidity and prolonged to GId.25 L-dopa can increase gastric acid secretion, impair
muscle contractions. gastric relaxation, and delay gastric emptying;14,26,27 anticho-
The role of sleep in early morning motor disturbances linergics and amantadine commonly cause dry mouth and
has not yet been clarified. In a recent study, 10–55% of constipation; and COMT inhibitors can cause diarrhoea.
patients with mild to moderate PD and a fluctuating response The association between morning akinesia and other
to L-dopa experienced a reduction in disability for 40–60 common NMSs which strongly impair health-related QoL,
minutes after waking.9 This improvement before drug intake such as fatigue, pain, and psychiatric disturbances,4 needs to
is known as sleep benefit, and may be due to an improvement be investigated. Nevertheless, improving NMSs should be
in dopaminergic function during sleep. Other “pharmacologic viewed as an important part in the management of PD.4,28
hypotheses” implicate drug-induced motor fluctuations,7 It has also been shown that regardless of the disease dura-
transient worsening after the first morning L-dopa dose,10 tion or severity of motor complications, not a single NMS but
and a competition between large neutral amino acids and the burden of “total” NMSs is the major determinant of QoL.28
L-dopa for transport access into the brain.8,11 Some symptoms such as fatigue, depression, and concentra-
Other symptoms have been recently associated with tion problems seem to contribute to this burden more than
morning akinesia, including post-prandial bloating, abdomi- others, since these occur both in “ON” and “OFF” periods.
nal discomfort, early satiety, nausea, vomiting, weight loss, Fatigue has emerged as a key NMS of PD, and its prevalence
and malnutrition,12,13 or in other words, gastroparesis is a reached almost 50% even in patients with early PD.4
consistent feature of gastrointestinal dysfunction (GId).14
GId in PD is due to both the underlying synucleinopathy Challenges and solutions
and dopaminergic therapy.15 Data suggest that the underlying Since the first descriptions of L-dopa-induced complica-
neurodegenerative process affects the central, autonomic, and tions,29,30 delayed ON, sleep disorders, and early morning OFF
enteric nervous systems. Features of GId include dry mouth, periods have always been controversial issues. Specifically,

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 Dovepress Morning akinesia in Parkinson’s disease

the optimization of traditional pharmacologic PD oral therapy minimal effects on the central nervous system, while at the
by itself may not be sufficient for alleviating symptoms. same time significantly improving gastric emptying without
Although it has been reported that 50% to 80% of PD affecting PD motor symptoms.14,25,27
patients develop motor complications within 5 to 10 years Long-acting dopamine agonists allow more stable and
from the beginning of L-dopa therapy,29 recent studies state continuous dopaminergic stimulation (CDS) and improve
that ∼50% of patients show motor complications within nocturnal disability. In previous studies, cabergoline, in
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2 years of treatment.31,32 particular, appeared to be more effective than the L-dopa

Standard oral L-dopa treatment is inadequate for the treat- controlled-release formulation in relieving nocturnal painful
ment of morning akinesia for reasons related to its pharma- dystonia, nocturnal and morning akinesia, and early morning
codynamics and pharmacokinetics and because have a short dystonia.45–48 Surprisingly, this improvement was associated
half-life, erratic gastrointestinal absorption, and competitive with a significant increase in the number of awakenings and
transport across the blood–brain barrier. stage shifts, as shown by polysomnography. The functional
L-dopa has a very poor solubility and its “end-of-dose” significance of this finding remains uncertain49 (Table 1).
deterioration is directly related to the level of plasma L-dopa. Bromocriptine, in combination with lower doses of
Therefore, one of the first strategies attempted to focus L-dopa, resulted in therapeutic response equal to that
on prolonging L-dopa plasma levels, using long-acting, achieved with high-dose L-dopa alone, but with significantly
controlled-release L-dopa preparations.33–36 Nevertheless, fewer end-of-dose failures and dyskinesia. At the end of
due to delayed gastric emptying, an oral dose of L-dopa may 5 years, early combination of L-dopa and bromocriptine
For personal use only.

remain in the stomach for a long time before being absorbed resulted in a reduced frequency of early morning akinesia
in the small intestine.33–36 and dose-related freezing of gait episodes.50,51
Another approach is administering L-dopa as a liquid More recently, continuous 24-hour delivery of a dop-
solution to reduce gastric transit time and improve the onset amine agonist has been reported as an attractive option for
of effect. This approach may be beneficial for some patients the management of PD patients with end-of-dose symptom
with severe fluctuations; however, the clinical benefits of liquid deterioration and specific complaints of nocturnal and early
L-dopa compared with tablets has not been confirmed in con- morning motor impairment.52
trolled clinical studies.37 To manage early morning akinesia and Moreover, prolonged release of dopamine agonists
episodes of nocturnal hypomobility, many patients use L-dopa medications (rotigotine, ropinirole, pramipexole) has been
on an intermittent or as-needed basis. However, the slow or associated with significantly less early morning OFF periods
unpredictable onset of effect limits the clinical benefit.38 compared with L-dopa therapy only.3
The addition of monoamine oxidase-B inhibitors and In 2010, the RECOVER study, a large-scale, double-blind,
COMT inhibitors may be helpful in prolonging the duration randomized trial reported 24-hour transdermal rotigotine treat-
of the efficacy of each single L-dopa dose.34,39,40 ment to be associated with significant benefits versus placebo
In addition to absorption delay due to slowed gastrointes- in the management of early morning motor impairment and
tinal transit, circulating diet-derived proteins may interfere nocturnal sleep disturbances. Rotigotine was also associated
with the transit of L-dopa across the blood–brain barrier and with improvements in nighttime disabilities (such as limb
in the gut.38,41–43 Dietary manipulation, such as reducing the restlessness, immobility, pain, and cramps), and possibly dop-
ingestion of protein to minimize L-dopa-protein competition aminergic nonmotor daytime symptoms (such as fatigue and
across cellular membrane transporters, may be attempted.35,44 mood) as well.53 In addition, the transdermal route bypasses the
Multiple small meals with low fat content and a reduction gastrointestinal tract and its associated motor fluctuations.
in the intake of indigestible fiber are considered as effective An improvement in sleep associated with rotigotine may be
nonpharmacological strategies for management of gastropa- the result of its effect on curbing nocturnal motor symptoms:
resis. If possible, medications that can slow gastric emptying limb restlessness, urge to move arms or legs, painful posturing
should be avoided. in the morning, and tremor on awakening. Likewise, reported
Pharmacological treatment of gastroparesis includes the improvement in painful posturing in the morning may be
use of prokinetic agents. Dopamine antagonists, such as the result of an early morning improvement in akinesia and
domperidone and metoclopramide, can also reduce gastric dystonia.53 Moreover, transdermal rotigotine demonstrated
emptying time. Compared to metoclopramide, domperidone efficacy and safety as monotherapy in early PD and in reducing
does not cross the blood–brain barrier, consequently having ‘‘OFF’’ hours in L-dopa-treated patients with advanced PD.54,55

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Table 1 Studies on the treatments managing morning akinesia

Authors Proposed treatments Pros Cons
Baas and Schueler 45
Cabergoline More effective than the CR-L-dopa in relieving Increase in the number of
Högl et al49 nocturnal painful dystonia, nocturnal and awakenings and stage shifts, and
morning akinesia, and early morning dystonia ergot-derived drug adverse events

Rinne50 Bromocriptine + L-dopa Reduced frequency of early morning akinesia and Ergot-derived drug adverse events
Rinne51 dose-related freezing of gait episodes
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Giladi et al52 Rotigotine Benefit in early morning motor impairment and Primes/worsens dyskinesia; ICD;
Trenkwalder et al53 sleep disturbances; transdermal administration cutaneous reactions

Chaudhuri et al56 Mirapexin and Improvements in sleep disturbances Primes/worsens dyskinesia;

Poewe et al57 ropinirole reduced absorption due to oral
administration

Trosch et al58 Apomorphine Rapid and reliable time-to-ON in patients with Self- administration of subcutaneous
Pfeiffer et al59 morning akinesia injection

Zibetti et al61 LCIG Improvement of nocturnal sleep quality, High costs, patients selection,
pain, muscle cramps, restlessness, and painful surgical risks
posturing in the morning

Arnulf et al62 STN DBS Improvement of sleep architecture and High costs, patients selection,
Hjort et al63 quality; alleviation of “OFF period” dystonia surgical risks
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Derrey et al64 after microlesion effect produced by surgical

intervention
Abbreviations: L-dopa, levodopa; CR-L-dopa, controlled release levodopa; LCIG, levodopa/carbidopa intestinal gel; STN DBS, subthalamic nuclei deep brain stimulation;
ICD, impulse control disorder.

Significant improvements in sleep disturbances have also been substantially with L-dopa/carbidopa intestinal gel (LCIG)
recorded with prolonged-release formulations of ropinirole54,56 infusion in advanced PD. Additionally, nocturnal sleep
and pramipexole.54,57 Though these medications have shown improved in all patients treated with LCIG compared with
their efficacy and safety in advanced PD,56,57 like L-dopa, they previous oral therapy. In particular, ameliorations in nocturnal
are administered orally and their capacity of inducing motor sleep quality, pain, muscle cramps, restlessness, and painful
complication is low. In fact, as with all dopaminergic drugs, posturing in the morning were reported.61
they may trigger the onset or worsen dyskinesias.40 Another small study reported improvements in sleep
Apomorphine is a potent short-acting dopamine D1 and architecture and quality, along with an increase in total sleep
D2 receptor agonist that can be administered subcutaneously time (up to 47%) even in patients treated with subthalamic
and is currently being used for the management of sudden, nuclei (STN) deep brain stimulation (DBS).62,63 Moreover, an
unexpected and refractory L-dopa-induced OFF states in alleviation of “OFF” dystonia was registered after the microle-
fluctuating PD either as intermittent rescue injections or con- sion effect produced by STN DBS surgical intervention. In
tinuous infusions.58–60 Apomorphine injections may be helpful this group of 30 patients, the morning of the third day follow-
in treating morning akinesia, since time-to-ON should not be ing STN implantation, after at least a 12-hour withdrawal of
affected by delayed gastric emptying due to gastroparesis. The dopaminergic treatment and before the programmable pulse
ongoing Phase IV, multicenter, open-label AM-IMPAKT trial generator was switched on, a significant clinical improvement
is investigating whether subcutaneous apomorphine injection was observed.64 Motor score of Unified Parkinson’s Disease
on awakening can provide improvement in motor and NMSs in Rating Scale improved by 27% and 12 patients reported
PD patients with morning akinesia. Interim results suggest that complete relief of their symptoms in the immediate postop-
apomorphine injection as an adjunctive therapy may provide a erative period, remaining free of painful off-period dystonia
rapid and reliable time-to-ON in patients with morning akinesia, throughout the 6-month follow-up period.64
resulting in significant improvements in QoL3,14 (Table 1). Yet, larger and more specific studies performed over lon-
CDS is a valid strategy in controlling both motor and ger periods of time are needed to fully evaluate the beneficial
NMSs in PD. A recent study on a small number of patients effects of LCIG therapy and STN DBS on both sleep and
reported that subjective measures of sleep quality improved early morning dystonia.

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 Dovepress Morning akinesia in Parkinson’s disease

Discussion 2. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the

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also believed to play underlying roles in both its maintenance Neurology. 2013;80(9):800–809.
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Disclosure 193–203.
22. Doi H, Sakakibara R, Sato M, et  al. Plasma levodopa peak delay
The authors report no conflicts of interest in this work. and impaired gastric emptying in Parkinson’s disease. J Neurol Sci.
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